Preferred compounds of the present invention are compounds of Formula I wherein R.sub.1 is isobutyl, benzyl, isobutyryl, benzoyl, 4-chlorobenzoyl, 4-methylbenzoyl or 2,4-dichlorobenzoyl, or any pharmaceutically acceptable salt of same, such as salts formed by nontoxic metal cations (for example, sodium, lithium, potassium, magnesium) or those formed with nontoxic organic bases of the amine type (ethanolamine, triethanolamine, lysine, etc.).
The process that is the subject of the present invention is characterized by the following scheme: ##STR2##
This process is characterized by using a 2-(3'-thienyl)malonic ester, preferably dimethyl-2-(3'-thienyl)malonate or diethyl-2-(3'-thienyl)malonate as raw material which, in a first step, is treated with methyl iodide for the purpose of methylating the CH group. The reaction is performed under solid-to-liquid phase transfer conditions, using as solid bases a mixture of potassium carbonate and potassium hydroxide. The organic solvent can be toluene, benzene or any solvent of low polarity, preferably the first mentioned. As the phase transfer catalyst any quaternary ammonium salt can be used that is suitable for this purpose, preferably tetrabutylammonium acid sulfate (TBAB).
In a second step the process consists in the hydrolysis of 2-methyl-2-(3'-thienyl)malonic ester by the conventional method, i.e., by refluxing the compound in a solution of potassium hydroxide in ethanol. During this process, partial decarboxylation of one of the carboxyl groups of the resultant 2-(3'-thienyl)malonic acid can also occur, which is isolated by conventional methods. The product of the hydrolysis is subjected, without preliminary treatment, to decarboxylation by heating in a vacuum of the order of 20 mm of mercury. Afterward, it is purified by vacuum distillation and the corresponding 2-3'-thienyl)propionic acid is obtained.
In a third step, this acid is treated with an appropriate acid chloride (e.g., isobutyryl chloride, benzoyl chloride, etc) under Friedel-Crafts conditions, i.e., in the presence of a Lewis acid type catalyst, preferably aluminum trichloride, in a suitable organic solvent such as methylene chloride, carbon sulfide, etc. After the treatment commonly practiced in this type of reactions, a raw product is arrived at which is thoroughly purified by crystallization, or by silica gel column chromatography, or by any of the methods commonly used in organic synthesis. In this manner the corresponding 2-(5'-acyl-3'-thienyl)propionic acids, which are the subject of the present invention, are obtained.
From these acyl compounds, the 2-(5'-alkyl-3'-thienyl)propionic acids, and 2-(5'-phenylalkyl-3'-thienyl)propionic acid compounds which are also subject matter of the present invention, can be obtained from those above by the Wolf-Kishner process, i.e., by prolonged boiling of the 2-(5'-acyl-3'-thienyl)-propionic acids in the presence of potassium hydroxide and ethylene glycol. After the treatment conventionally practiced in this type of reaction, the final product is purified by high-vacuum distillation or by column chromatography on silica.
The compounds of the present invention, especially 2-5'-benzoyl-3'-thienyl)propionic acid (I) and 2-(5'-(4"-chlorobenzoyl)-3'-thienyl)propionic acid (II), have an anti-inflammatory activity in mammals, and therefore they are useful in the treatment of arthritis, rheumatism, and other inflammatory type diseases. ##STR3##
The pharmacological tests were performed on rats and mice, using the carrageenin edema procedure on rats' legs and backs by the test for anti-inflammatory action and the acetic acid contorsion and hot plate tests on mice for the purpose of testing analgesic action.
In the anti-inflammatory action test, the test was performed on rat leg edema induced by carrageenin, administering the compounds per os and measuring the volume of the edema 3 hours later by plethysmography.
The anti-inflammatory action of these compounds was also examined by the carrageenin abscess test on rats' backs, the abscess being weighed 24 hours after administration of the product.
The results obtained in both tests are expressed as a percentage of inhibition of the edema or abscess, and were better than 30% in comparison with a control group.
For the examination of analgesic action, the acetic acid and hot plate tests were used.
In both tests the analgesic activity of these compounds is evaluated by the greater or lesser degree of inhibition of the chemical or thermal pain stimulus.
In the acetic acid test, the number of contorsions (stretching) is determined, which are produced for 30 minutes following intraperitoneal administration of dilute acetic acid. Analgesic action is also tested by the hot plate test in which the pain stimulus is thermal, the time being measured in seconds which the animal takes to respond to the stimulus by licking its feet.
The results obtained in both test, in harmony with the anti-inflammatory action tests, shows that these compounds, especially I and II, have an analgesic action.
The pharmacological action of all these compounds is manifested in oral and parenteral administration, although it is also evident in rectal and topical or local administration.
The dosages can vary from minimums of 6.25 mg/kg to maximums of 100 mg/kg. However, these are very far from the LD.sub.50 (400 to 1500 mg/kg), and yet they have ample therapeutic indications.
The greater or lesser intensity of action depends on the radical R.sub.1, the benzoyl radical being the one of greatest activity. Also, the presence or absence of halogen radicals in the benzoyl group has an influence. This is shown by the good results obtained with compound I and by its low median effective dose (ED.sub.50), which confirms its notable analgesic and anti-inflammatory action. As for its monohalogenated derivative II, it too has a notable pharmacological action, though it is inferior to that of compound I.
The rest of the compounds tested have a variable action of a fugitive character, compound IV (Example 7) being the best representative of this action due to its great similarity to compound II, which confirms the superiority of the benzoyl radical over others (isobutyl, for example).
In man, the usual daily dose of these compounds, preferably compounds I and II, can vary from 0.5 mg to 25 mg per kilogram, t.i.d., averaging 10 mg/kg.
Therefore, the process of the present invention serves for obtaining, preferentially, the two compounds A and B of the formulae ##STR4## whose potent anti-inflammatory activity can make them useful anti-inflammatory agents.